This proposal describes the examination of a large cohort of persons who are at high risk for age-related macular degeneration (AMD) by virtue of their age. The cohort will have been under observation for 20 years allowing us to capitalize on the unique ability to: (1) determine the association of AMD with long and varying exposure to risk factors, some measured from the baseline examination (e.g., blood pressure, smoking, cardiovascular disease, markers of anti-oxidant stress) and some measured from 5, 10, or 15 years prior to the current examination (e.g., carotid artery intima-media thickness and plaques peak expiratory flow rate) as well as with changes in exposure levels over past time intervals; (2) determine the risk of AMD associated with specific polymorphisms in known and novel gene regions and to estimate population attributable risk for these sites; (3) determine gene/environment and gene/host interactions for AMD in the Beaver Dam cohort and in a pooled data set from 3 populations (Beaver Dam, Blue Mountains and Rotterdam) of European ancestry; and (4) examine the natural history of AMD and other retinal diseases (e.g., retinal vein occlusion; diabetic retinopathy) through cumulative 20 year incidence, regression, progression, age-period-cohort models and transitional state models. This approach is crucial for chronic diseases where risk factors are likely to exert their influence over a long period of time and where important ocular events evolve over a prolonged interval. This unique study will permit us to investigate new hypotheses about the correlates of AMD and other less common visually impairing retinal conditions. The information we will gain is of importance in understanding determinants of these retinal diseases and is needed for early diagnosis, prognosis, and for developing interventions to prevent visual loss from these conditions.